Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease are increasingly common due to aging of the human population. These diseases are known as “proteinopathies”, as they are characterized by the dysfunction of specific proteins, leading to extracellular and intracellular accumulation of protein aggregates.
Alzheimer's disease (AD) is the most common form of dementia worldwide. Recent data show an exponential increase in the number of cases of Alzheimer's patients, emphasizing the need to develop effective treatments. Today about 35.6 million people worldwide live with this disease; by 2050 it is expected that the numbers reach close to 115 million. Indeed, the sector with highest growth potential in the pharmaceutical industry concerns developing drugs for neurological disease.
AD is characterized neuropathologically by accumulation of beta-amyloid peptide (BAP), which results from the processing of amyloid precursor protein (APP). BAP forms the main component of senile plaques, which are the starting point of AD pathogenesis.
Although, in recent years, there have been advances in understanding and treating brain pathologies, many disorders of the central nervous system (CNS), including AD, continue to be devastating and poorly treatable. One problem in treating these disorders is that many drug are unable to cross the blood-brain barrier (BBB) to reach the CNS, a problem especially seen with large molecule drugs. The BBB is formed by specialized endothelial cells (brain endothelial cells) that line capillaries supplying the brain and which prevent, or hinder, the passage of substances from the blood into the CNS.
Various approaches have been attempted to overcome this difficulty. For example, controlled release systems have been used, but these systems sometimes interfere with the operation of the BBB. Another approach involves developing lipophilic drugs, but these have the disadvantage of being rapidly excreted into the bloodstream. Surgical procedures to temporarily open the barrier also have been tested, for example using mannitol injections to decrease cell size and leave voids between the cells, but such procedures may be unsafe, potentially causing swelling, convulsion, and increased susceptibility to infection. Still another approach to deliver drugs across the BBB involves linking the drug to an antibody specific for receptors on the BBB, such as the insulin, leptin, or transferrin receptor, and taking advantage of existing “portals” across the BBB using receptor mediated cytosis. Nonetheless, delivery using this approach is limited by receptor saturation and poor penetration into the extravascular tissue. Moreover, these receptors are expressed in other tissues and are implicated in metabolically critical cellular functions, creating safety risks.
An alternative approach involves using cell-penetrating peptides (CPPs), having translocation capacity. Following the discovery that the third helix of Antennapedia homeodomain crosses biological membranes, investigators have studied different CPPs capable of carrying various cargo loads to the interior of cells, including low molecular weight drugs, liposomes, plasmids, antibodies, and nanoparticles. Nonetheless, use of CPPs as delivery systems is limited by a lack of cell specificity in CPP-mediated cargo delivery.
Further, having crossed the BBB, it is advantageous for a therapeutic to exert its therapeutic effect, and then be efficiently cleared from the brain and CNS and returned to the general circulation for elimination from a patient's body.
Accordingly, there remains a need in the art for therapeutics for treating and managing AD, and related disorders, in particular, a need for therapeutics capable of crossing the BBB specifically and then being cleared therefrom efficiently, as well as delivery systems that safely deliver therapeutics across the barrier to the CNS. There also remains a need for effective diagnosis of initial and late stages of AD. The instant invention addresses these and other needs.